Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein, Dr. Priya Duggal, Dr. Alison Klein and Dr. Sudha Iyengar on analyses of existing family data from the Beaver Dam Eye Study (BDES). A private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. We have previously analyzed STRP genome-wide scan (GWS) data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. Linkage analyses using a new SNP linkage panel with multiple traits including: refraction, myopia was previously performed. Genotype data from the whole exome SNP array is being analyzed by Dr. Duggal in the families and unrelated individuals in this cohort and both linkage and association analyses will be performed for various eye disease traits. In addition this study has joined the Consortium for Refractive Error and Myopia (CREAM), a consortium of over 50 international studies who will work together to perform meta-analyses of refractive error traits. A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 populations. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1. A set of about 1500 SNPs were genotyped in our Ashkenazi and Amish families to follow up the linkage of refractive error on chromosome 1; these analyses confirmed our previous linkage of refractive error to a locus on 1p34-p36. We have analyzed additional deep sequencing data of this region in the past and are currently performing confirmatory studies of a candidate mutation. We have recently published results of a genome-wide association study (GWAS) of refractive error in the AREDS, KORA, Framingham Eye Study (FES), the MESA study and the OGP-Talana study in Sardinia, with confirmation of the discoveries from these data in several other GWAS. During this year we have also performed similar analyses of myopia and hyperopia and a paper is under review. Whole exome SNP array genotyping was performed in all of the Family Myopia Study families, the AREDS cohort and an additional 4000 unrelated individuals. We are analyzing these data using multiple approaches to detect rare variants that contribute to refractive error traits. Dr. Bailey-Wilson is also one of the leaders of CREAM, an international consortium on meta-analysis of refractive error related traits and is co-Chair of CREAM Analysis Working Group 2. The collaborative analyses planned by CREAM will increase power to detect common alleles with small effects on refractive error as a quantitative trait and its related clinical disorders, myopia, hyperopia and astigmatism. This year we performed analyses on our AREDS, KORA and FES GWAS data for a meta-analysis of refractive error by the CREAM consortium and were co-authors on a paper in Nature Genetics presenting these results. In this year, we are also co-authors of a CREAM paper on genetic loci affecting the variation of axial length 1. Dr. Bailey-Wilson is co-leading the CREAM study of astigmatism with Dr. Jeremy Guggenheim and a first manuscript is under review. We have also completed analyses of myopia on the AREDS data for the next CREAM meta-analysis and are planning a second astigmatism meta-analysis. Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic and Dr. Terri Beaty of Johns Hopkins Bloomberg School of Public Health on studies of oral clefts. We have recently performed a study attempting to identify gene-gene interactions within the WNT pathway for nonsyndromic oral clefts (with or without cleft palate) using Asian and European trio data. This project used some methods newly developed by our group as part of another Annual Report and a manuscript is under review. We are currently analyzing whole-exome and whole-genome sequence data of selected members of our multiplex pedigrees. A first paper presenting some of our WES results was published this year 2 and analyses are ongoing. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NICHD/NIH and Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Evidence for excess hypocholesterolemia in autistic individuals has been observed in some multiplex families Special funding from the Office of the Director was sought and awarded to perform whole-exome sequencing of autistic patients with extreme cholesterol values and a sibling with either autism or autism spectrum disorder (ASD) to search for rare variants of large effect in this subset of patients with familial autism/ASD. Whole exome sequence data for all of the families is now being analyzed. Since the data were sequenced over a long time period, we are recalling all the data together and analyses will be ongoing over the next year. We are also collaborating with Drs. Sue Swedo and Audrey Thurm of NIMH/NIH to analyze WES of their very well phenotyped parent-child trios and families where at least one child is affected with autism. All of these data have now been sequenced and analyses are underway. Utilizing the sequence data from this project as controls (along with othet datasets) we published a paper this year that estimated the frequency of risk alleles for Smith-Lemli-Opitz syndrome in unselected individuals 3. Dr. Bailey-Wilson is collaborating with Dr. John Heiss on a study of Chiari Syndrome in Russia. This rare neurological syndrome is observed at increased frequency in several large families from a founder region there. Linkage analyses have been completed in these families and analyses of DNA sequencing to follow-up the most significant results are ongoing. Dr. Bailey-Wilson is also collaborating with Dr. Larry Brody and Dr. Alexander Wilson of NHGRI on analyses of GWAS data on metabolic traits in the Trinity Study of healthy young adults. This work is ongoing, several papers are in preparation and one paper is under review. Dr. Claire Simpson, a Staff Scientist in my Section, has continued a collaboration with her PhD thesis advisor and was a coauthor on a paper concerning the effects of phospholipase C delta 1 on survival in SOD1G93A mice 4. Dr. Simpson has also initiated a collaboration with Dr. Steve Brant of Johns Hopkins School of Medicine and is analyzing GWAS data on 500 African American Crohn's Disease patients. She has completed linkage analyses on 12 members of a Jewish Crohn's Disease pedigree and follow-up is ongling. She and Dr. Brant plan to perform exome sequencing, DNA methylation and RNASeq expression analysis in affected sib pairs from his collection of Jewish families with Crohn's Disease. She is currenlty working on GWAS and admixture studies. Dr. Cheryl Cropp, a Research Fellow in my group, has collaborated with Matt Gribble at Johns Hopkins to publish a study of SLC01B1 variants in the Strong Heart